Dr Martin Nicklin
MA, PhD
Clinical Medicine, School of Medicine and Population Health
Senior Lecturer
+44 114 215 9541
Full contact details
Clinical Medicine, School of Medicine and Population Health
The Medical School
Beech Hill Road
Sheffield
S10 2RX
- Profile
-
For enquiries please contact - ClinMed-Operational@sheffield.ac.uk
I joined the University of Sheffield in October 1992 after studying for a PhD from 1980-1983, working on the biochemistry of cystatins (cysteine proteinase inhibitors) with Alan Barrett in Cambridge.
Then from 1984-1987 worked as a post-doctoral Damon Runyon-Walter Winchell fellow at SUNY Stony Brook with Eckard Wimmer on the replication of poliovirus (the connection being the viral cysteine proteinases) and then between 1988 and 1991 as a Junior Scientist at the Institute for Molecular Pathology in Vienna, where I worked on DNA-binding proteins Fos and Jun.
I began work at the University of Sheffield on mapping, discovering and searching for the functions of interleukin-1-like proteins (which we surmised would exist and would also be important!) in mouse and human.
My research pathway has been from protein biochemistry through molecular biology into genetics and immunology.
- Research interests
-
Interleukin-1 is powerful pleiotropic pro-inflammatory signalling protein that has been known since the early 1980s. However, its unique biological activity has really started to be identified in the past five years.
IL-1 has a single known functional receptor and another IL-1-like protein, IL-1 receptor antagonist (IL-1Ra) binds the receptor as a competitive inhibitor.
In collaboration with Austin Smith, we developed IL-1Ra-deficient mice and my group and collaborators have characterised two of the chronic inflammatory phenotypes that these mice develop.
Our mutations are available on BALB/c and C57BL/6 backgrounds. The strains develop different autoimmune conditions including elastic-vessel vasculitis, a psoriasis-like a skin inflammation and rheumatoid arthritis-like disease.
One of the most interesting findings, in collaboration with Leo Joosten and colleagues in Nijmegen, was the demonstration that early onset arthritis in the BALB/c strain is dependent on specific gut colonisation by microbes.
We had long suspected a microbial trigger on the basis of the timing and clustering of disease onset.
My other research interest is in defining the critical biological function of a group of IL-1-like proteins that now are collectively known as IL-36, whose genes we had previously helped identify and map.
We are working to identify essential functions that have led to active IL-1-like genes being present in all sequenced mammalian genomes and yet are specific to mammals.
I have recently been engaged in producing SARS-CoV2 antigens for Clinical Seroconversion assays in collaboration with colleagues in the Department and in the NHS Trust.
Current Projects:
- Identifying the connection between IL-1Ra-deficiency and chronic inflammatory diseases.
- Finding the essential biological functions of members of the interleukin-1 family of cytokines.
- Publications
-
Show: Featured publications All publications
Featured publications
Journal articles
- Interleukin-1 receptor antagonist deficient mice provide insights into pathogenesis of human intervertebral disc degeneration.. Ann Rheum Dis, 72(11), 1860-1867.
- Impact of IL-1 signalling on experimental uveitis and arthritis.. Ann Rheum Dis, 71(5), 753-760.
- Interleukin-1β regulates CXCL8 release and influences disease outcome in response to Streptococcus pneumoniae, defining intercellular cooperation between pulmonary epithelial cells and macrophages.. Infect Immun, 80(3), 1140-1149. View this article in WRRO
- Finally, function for "IL-1Fs".. Blood, 118(22), 5713-5714.
- Alterations in the self-renewal and differentiation ability of bone marrow mesenchymal stem cells in a mouse model of rheumatoid arthritis.. Arthritis Res Ther, 12(4), R149. View this article in WRRO
- Interleukin-1 drives pathogenic Th17 cells during spontaneous arthritis in interleukin-1 receptor antagonist-deficient mice.. Arthritis Rheum, 58(11), 3461-3470.
- Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis.. J Clin Invest, 118(1), 205-216.
- Decreased fat mass in interleukin-1 receptor antagonist-deficient mice: impact on adipogenesis, food intake, and energy expenditure.. Diabetes, 54(12), 3503-3509.
- Elastic-vessel arteritis in interleukin-1 receptor antagonist-deficient mice involves effector Th1 cells and requires interleukin-1 receptor.. Circulation, 111(23), 3135-3140.
- Psoriasis-like cutaneous inflammation in mice lacking interleukin-1 receptor antagonist.. J Invest Dermatol, 122(3), 665-669.
- A sequence-based map of the nine genes of the human interleukin-1 cluster.. Genomics, 79(5), 718-725.
All publications
Journal articles
- High SARS-CoV-2 incidence and asymptomatic fraction during Delta and Omicron BA.1 waves in The Gambia. Nature Communications, 15(1). View this article in WRRO
- Establishing SARS-CoV-2 Membrane protein-specific antibodies as a valuable serological target via high-content microscopy. iScience, 107056-107056.
- Risk factors for SARS-CoV-2 seroprevalence following the first pandemic wave in UK healthcare workers in a large NHS Foundation Trust. Wellcome Open Research, 6, 220.
- Evidence that all Sorsby's fundus dystrophy mutations cause TIMP3 dimerization resulting in impaired inhibition of VEGFR2. Genes and Diseases.
- Risk factors for SARS-CoV-2 seroprevalence following the first pandemic wave in UK healthcare workers in a large NHS Foundation Trust. Wellcome Open Research, 6. View this article in WRRO
- Long-range DNA interactions at the IL-1/IL-36/IL-37 gene cluster (2q13) are induced by activation of monocytes.. Cytokine, 68(1), 16-22.
- Interleukin-1 receptor antagonist deficient mice provide insights into pathogenesis of human intervertebral disc degeneration.. Ann Rheum Dis, 72(11), 1860-1867.
- Intracellular function of interleukin-1 receptor antagonist in ischemic cardiomyocytes.. PLoS One, 8(1), e53265. View this article in WRRO
- Impact of IL-1 signalling on experimental uveitis and arthritis.. Ann Rheum Dis, 71(5), 753-760.
- Interleukin-1β regulates CXCL8 release and influences disease outcome in response to Streptococcus pneumoniae, defining intercellular cooperation between pulmonary epithelial cells and macrophages.. Infect Immun, 80(3), 1140-1149. View this article in WRRO
- Finally, function for "IL-1Fs".. Blood, 118(22), 5713-5714.
- Alterations in the self-renewal and differentiation ability of bone marrow mesenchymal stem cells in a mouse model of rheumatoid arthritis.. Arthritis Res Ther, 12(4), R149. View this article in WRRO
- Interleukin-1 drives pathogenic Th17 cells during spontaneous arthritis in interleukin-1 receptor antagonist-deficient mice.. Arthritis Rheum, 58(11), 3461-3470.
- Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis.. J Clin Invest, 118(1), 205-216.
- Interleukin-1 receptor antagonist is upregulated during diet-induced obesity and regulates insulin sensitivity in rodents.. Diabetologia, 49(2), 387-393.
- The new IL-1 family member IL-1F8 stimulates production of inflammatory mediators by synovial fibroblasts and articular chondrocytes.. Arthritis Res Ther, 8(3), R80. View this article in WRRO
- Decreased fat mass in interleukin-1 receptor antagonist-deficient mice: impact on adipogenesis, food intake, and energy expenditure.. Diabetes, 54(12), 3503-3509.
- Elastic-vessel arteritis in interleukin-1 receptor antagonist-deficient mice involves effector Th1 cells and requires interleukin-1 receptor.. Circulation, 111(23), 3135-3140.
- Psoriasis-like cutaneous inflammation in mice lacking interleukin-1 receptor antagonist.. J Invest Dermatol, 122(3), 665-669.
- Toll-like receptor 2 and 4 (TLR2 and TLR4) agonists differentially regulate secretory interleukin-1 receptor antagonist gene expression in macrophages.. J Biol Chem, 277(20), 17448-17456. View this article in WRRO
- A sequence-based map of the nine genes of the human interleukin-1 cluster.. Genomics, 79(5), 718-725.
- Genetic analysis of the interleukin-1 receptor antagonist and its homologue IL-1L1 in alopecia areata: strong severity association and possible gene interaction.. Eur J Immunogenet, 29(1), 25-30.
- Annotating genes with potential roles in the immune system: six new members of the IL-1 family.. Trends Immunol, 22(10), 533-536.
- A new nomenclature for IL-1-family genes.. Trends Immunol, 22(10), 536-537.
- A tissue specific IL-1 receptor antagonist homolog from the IL-1 cluster lacks IL-1, IL-1ra, IL-18 and IL-18 antagonist activities.. Eur J Immunol, 30(11), 3299-3308.
- Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene.. J Exp Med, 191(2), 303-312. View this article in WRRO
- Interleukin-1 receptor cluster: gene organization of IL1R2, IL1R1, IL1RL2 (IL-1Rrp2), IL1RL1 (T1/ST2), and IL18R1 (IL-1Rrp) on human chromosome 2q.. Genomics, 57(1), 177-179.
- An analysis of linkage disequilibrium in the interleukin-1 gene cluster, using a novel grouping method for multiallelic markers.. Am J Hum Genet, 62(5), 1180-1188.
- The human gene encoding the interleukin-1 receptor accessory protein (IL1RAP) maps to chromosome 3q28 by fluorescence in situ hybridization and radiation hybrid mapping.. Genomics, 47(2), 325-326.
- A mammalian homolog of the bacterial monomeric sarcosine oxidases maps to mouse chromosome 11, close to Cryba1.. Genomics, 46(3), 480-482.
- An analysis of linkage disequilibrium in the interleukin-1 gene cluster.. AMERICAN JOURNAL OF HUMAN GENETICS, 61(4), A272-A272.
- Molecular cloning of the interleukin-1 gene cluster: construction of an integrated YAC/PAC contig and a partial transcriptional map in the region of chromosome 2q13.. Genomics, 41(3), 370-378.
- SEZ-6: promoter selectivity, genomic structure and localized expression in the brain.. Brain Res Mol Brain Res, 44(2), 309-322.
- Novel interleukin-1 receptor antagonist exon polymorphisms and their use in allele-specific mRNA assessment.. Hum Genet, 97(6), 723-726.
- Novel interleukin-1 receptor antagonist exon polymorphisms and their use in allele-specific mRNA assessment. Human Genetics, 97(6), 723-726.
- Physical mapping of the gene for juvenile nephronophthisis (NPH1) by construction of a complete YAC contig of 7 Mb on chromosome 2q13. Cytogenetic and Genome Research, 73(3), 235-239.
- Novel microsatellite markers in the interleukin-1 gene cluster. CYTOGENETICS AND CELL GENETICS, 73(4), 3-3.
- A physical map of the region encompassing the human interleukin-1 alpha, interleukin-1 beta, and interleukin-1 receptor antagonist genes.. Genomics, 19(2), 382-384.
- Report of the Third International Workshop on Human Chromosome 2 Mapping 1994. Cytogenetic and Genome Research, 67(4), 215-244.
- ANALYSIS OF THE INTERLEUKIN-1 GENE-CLUSTER. CYTOGENETICS AND CELL GENETICS, 67(4), 243-243.
- Accumulated helix-destabilizing mutations in the leucine zipper of c-Fos leads to attenuation and temperature sensitivity of function.. Oncogene, 8(7), 1737-1749.
- Purification and characterization of poliovirus polypeptide 3CD, a proteinase and a precursor for RNA polymerase.. J Virol, 66(12), 7481-7489.
- A single site mutation in a truncated Fos protein allows it to interact with the TRE in vitro.. Oncogene, 6(1), 173-179.
- Cleavage of synthetic peptides by purified poliovirus 3C proteinase.. J Biol Chem, 264(17), 9738-9741.
- Poliovirus proteinase 3C: large-scale expression, purification, and specific cleavage activity on natural and synthetic substrates in vitro.. J Virol, 62(12), 4586-4593.
- A segment of the 5' nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation.. J Virol, 62(8), 2636-2643.
- Polyprotein processing in picornavirus replication.. Biochimie, 70(1), 119-130.
- Poliovirus proteinase 2A induces cleavage of eucaryotic initiation factor 4F polypeptide p220.. J Virol, 61(9), 2711-2718.
- Poliovirus polypeptide precursors: expression in vitro and processing by exogenous 3C and 2A proteinases.. Proc Natl Acad Sci U S A, 84(12), 4002-4006.
- Molecular Events Leading to Poliovirus Genome Replication. Cold Spring Harbor Symposia on Quantitative Biology, 52(0), 343-352.
- Molecular events leading to picornavirus genome replication.. J Cell Sci Suppl, 7, 251-276.
- Implications of the picornavirus capsid structure for polyprotein processing.. Proc Natl Acad Sci U S A, 84(1), 21-25.
- A second virus-encoded proteinase involved in proteolytic processing of poliovirus polyprotein.. Cell, 45(5), 761-770.
- Proteolytic Processing in the Replication of Polio and Related Viruses. Nature Biotechnology, 4(1), 33-42.
- The proteolytic activities of chymopapain, papain, and papaya proteinase III.. Biochim Biophys Acta, 828(2), 196-204.
- Inhibition of cysteine proteinases and dipeptidyl peptidase I by egg-white cystatin.. Biochem J, 223(1), 245-253.
- Similarity in gene organization and homology between proteins of animal picornaviruses and a plant comovirus suggest common ancestry of these virus families.. Nucleic Acids Res, 12(18), 7251-7267.
- Cystatin, a protein inhibitor of cysteine proteinases. Improved purification from egg white, characterization, and detection in chicken serum.. Biochem J, 211(1), 129-138.
- Risk factors for SARS-CoV-2 seroprevalence following the first pandemic wave in UK healthcare workers in a large NHS Foundation Trust. Wellcome Open Research, 6, 220-220.
- ACE2-Independent Interaction of SARS-CoV-2 Spike Protein with Human Epithelial Cells Is Inhibited by Unfractionated Heparin. Cells, 10(6), 1419-1419.
Chapters
- IL-1 Receptor Antagonist-Deficient Mice In Fantuzzi G (Ed.), Cytokine Knockouts (pp. 111-134). Humana Press
- Proteolytic Processing of the Poliovirus Polyprotein by Two Virus-Encoded Proteinases, Protein Engineering (pp. 319-337). Elsevier
Conference proceedings papers
- The Discordant Impact of IL-1 Signaling on Experimental Uveitis and Arthritis.. ARTHRITIS AND RHEUMATISM, Vol. 63(10) (pp S26-S26)
- The new IL-1 family member IL-1F8 stimulates the production of inflammatory mediators by synovial fibroblasts and articular chondrocytes. ANNALS OF THE RHEUMATIC DISEASES, Vol. 65 (pp 77-78)
- Inflammatory diseases in interleukin-1 receptor antagonist-deficient mice.. European Cytokine Network(11) (pp 200-200)
Preprints
- A high content microscopy-based platform for detecting antibodies to the nucleocapsid, spike and membrane proteins of SARS-CoV-2, Cold Spring Harbor Laboratory.
- Risk factors for SARS-CoV-2 seroprevalence following the first pandemic wave in UK healthcare workers in a large NHS Foundation Trust.
- Purification of recombinant SARS-CoV-2 spike, its receptor binding domain, and CR3022 mAb for serological assay.
- ACE2-independent interaction of SARS-CoV-2 spike protein to human epithelial cells can be inhibited by unfractionated heparin.
- Teaching interests
-
Currently my major teaching interest is in leading, developing and teaching the MSc in Molecular Medicine.
In 2010 our team (François Guesdon, Jon Shaw, Helen Marriott, Ilaria Bellantuono, Janine Kirby, Jane Shields and myself) won the Senate Award for 'Excellence in Collaboration in Teaching'.
We teach students up-to-date knowledge and technology. We also see the course as a means to develop students' skills in reading, thinking and writing like scientists.
This is an intense one-year masters course, featuring six months of taught modules and five months of lab work on an individual (selected) project.
The course is designed to train appropriate graduates in the reality of doing novel scientific research. We have taken on 420 students over the six years that I have led the course.
The course currently has pathways in "Genetic Mechanisms", "Experimental Medicine", "Neuroscience", "Cancer", "Cardovascular" and "Microbes and Infection".
Students can chose pathways after they have been with us for 10 weeks. I personally run modules entitled "From Genome to Gene Function" (MED6002) and "Genome and Sequence Analysis" (MED6005) which will also be available as Doctoral development modules, and I teach on two other modules as well as regularly supervising laboratory projects.
- Professional activities and memberships
-
I am a long standing and active member of the University's Local Genetic Modification Committee and I sit on the School and Faculty Postgraduate Taught Programmes Committees.
I am Chair of the University of Sheffield Biosafety Sub-committee.