Autoimmune rheumatologic diseases

Poster

Complement c1q Limits Osteoarthritis Pathology by Regulating Macrophage Activation

Thursday, June 15
5:45 PM - 7:00 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

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    Harini Raghu

    Stanford University; VA Palo Alto Health Care System

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      Qian Wang

      Stanford University; VA Palo Alto Health Care System

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        Heidi Wong

        Stanford University; VA Palo Alto Health Care System

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          Nithya Lingampalli

          Stanford University; VA Palo Alto Health Care System

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            Rong Mao

            Stanford University; VA Palo Alto Health Care System

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              William H. Robinson

              Stanford University; VA Palo Alto Health Care System

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