Autoimmune rheumatologic diseases

Oral Abstract Sessions

Complement C1q Limits Osteoarthritis Pathology By Regulating Macrophage Activation

Thursday, June 15
4:00 PM - 4:15 PM

Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability. While it is clear that OA pathogenesis involves low-grade inflammation, the precise immune mechanisms underlying this inflammation remain unknown. The complement component C1q is known to regulate inflammation via mechanisms involving apoptotic cell clearance and macrophage activation. We tested the hypothesis that C1q is a negative regulator of inflammation in OA by surgically inducing osteoarthritis in C1q-deficient (C1qa-/-) and wildtype (WT) mice and found that C1qa-/- mice develop exacerbated cartilage damage relative to WT controls. qPCR analyses of bone marrow-derived macrophages from C1qa-/- or WT mice, differentiated in sera with or without C1q, revealed that while WT macrophages grown in C1q-containing sera mounted a balanced pro-inflammatory vs anti-inflammatory response to cartilage debris stimulation, those differentiated in C1qa-/- sera had an enhanced pro-inflammatory response. Further, we found that C1qa-deficient macrophages grown in C1qa-/- sera had a markedly exaggerated pro-inflammatory phenotype which was partially reversed by growing C1qa-deficient macrophages in WT sera. Similarly, in vitro analyses of human macrophages stimulated with cartilage debris showed that macrophages differentiated in C1q-depleted serum exhibited an enhanced pro-inflammatory phenotype compared to those differentiated in normal human serum containing C1q, suggesting that serum C1q limits macrophage activation in vitro. Furthermore, we found that C1q elicits its immunoregulatory role via phosphorylation/activation of the ITIM-containing receptor, LAIR1 and the downstream adaptor, SHP1. Together, our data suggest that the C1q/LAIR1/SHP1 axis regulates unrestrained macrophage activation and limits inflammation and cartilage damage in osteoarthritis.

Bryan J. Cannon

Stanford University; VA Palo Alto Health Care System

Presentation(s):

Send Email for Bryan Cannon

Harini Raghu

Stanford University; VA Palo Alto Health Care System

Presentation(s):

Send Email for Harini Raghu

Qian Wang

Stanford University; VA Palo Alto Health Care System

Presentation(s):

Send Email for Qian Wang

Heidi Wong

Stanford University; VA Palo Alto Health Care System

Presentation(s):

Send Email for Heidi Wong

Nithya Lingampalli

Stanford University; VA Palo Alto Health Care System

Presentation(s):

Send Email for Nithya Lingampalli

Rong Mao

Stanford University; VA Palo Alto Health Care System

Presentation(s):

Send Email for Rong Mao

William H. Robinson

Associate Professor
Stanford University

Dr. Robinson is an Associate Professor of Medicine at Stanford University, and a Staff Physician at VA Palo Alto. The Robinson laboratory works in the fields of B cell biology, autoimmunity and inflammation. Dr. Robinson pioneered development of protein arrays, lipid arrays, and most recently high-throughput sequencing approaches to identify the targets of antibody responses, investigate mechanisms underlying disease, and to develop novel therapeutic approaches. Dr. Robinson is the Director of the Stanford Osteoarthritis Initiative, PI of the NIH Stanford AMP Technology Center, and Co-Director of the Stanford-UCSF Arthritis Foundation Center of Excellence. He co-founded the Stanford Human Immune Monitoring Center, serves on the editorial boards of several journals, and serves on the Board of Directors of the American College of Rheumatology. He is an inventor on 23 patent applications, and technologies developed in his Stanford and VA laboratories have been licensed to nine companies in the biotechnology industry. Dr. Robinson was elected to the American Society for Clinical Investigation and the Henry Kunkel Society. Dr. Robinson received his MD and PhD degrees from Stanford University, and completed his clinical training in internal medicine at UCSF.

Presentation(s):

Send Email for William Robinson


Assets

Complement C1q Limits Osteoarthritis Pathology By Regulating Macrophage Activation



Attendees who have favorited this

Send Email for Complement C1q Limits Osteoarthritis Pathology By Regulating Macrophage Activation