Blood. 2016 Nov 3;128(18):2218-2228.

C1q and HMGB1 reciprocally regulate human macrophage polarization.

Son M1, Porat A1,2, He M3, Suurmond J1, Santiago-Schwarz F1, Andersson U4, Coleman TR5, Volpe BT6, Tracey KJ7, Al-Abed Y3, Diamond B1.

1Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, NY.

2The Elmezzi Graduate School of Molecular Medicine, Northwell Health, Manhasset, NY.

3Center for Molecular Innovation, The Feinstein Institute for Medical Research, Manhasset, NY.

4Department of Women’s and Children’s Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

5The Feinstein Institute for Medical Research, Manhasset, NY.

6Laboratory of Functional Neuroanatomy, and.

7Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY.

 

 Abstract

A healthy immune system results from a balance of stimulatory and inhibitory pathways that allow effective responses to acute insults, without descending into chronic inflammation. Failed homeostasis is characteristic of autoimmune diseases such as systemic lupus erythematosus. Although HMGB1 induces proinflammatory M1-like macrophage differentiation, we describe a mechanism by which C1q modulates this activity and collaborates with HMGB1 to induce the differentiation of monocytes to anti-inflammatory M2-like macrophages. These anti-inflammatory macrophages are unresponsive to dendritic cell induction factors, effectively removing them from participation in an adaptive immune response. This pathway is mediated through a complex with RAGE and LAIR-1 and depends on relative levels of C1q and HMGB1. Importantly, these data provide insight into a homeostatic mechanism in which C1q and HMGB1 can cooperate to terminate inflammation, and which may be impaired in C1q-deficient patients with autoimmune disease. © 2016 by The American Society of Hematology.

PMID: 27683415

 

Study Highlight:

Considering that the overwhelming proportion of C1q deficient patients acquire  Systemic Lupus Erythematosus (SLE), our group has been focused on defining the immunoregulatory mechanism of C1q that is clearly important in safeguarding an appropriately regulated immune response (1,2). In this study, we have explored the relationship between C1q and the danger signal, High Mobility Group Box 1 (HMGB1) on human monocyte activation and differentiation (3).

HMGB1 is an evolutionarily ancient DNA-binding nucleoprotein and functions as a critical co-factor for the activation of endosomal Toll-like receptors (TLRs) in SLE (4). When bound to the Receptor for Advanced Glycation Endproducts (RAGE), it facilitates the transport of RNA and DNA to endosomal TLRs, leading to the production of type 1 interferon (IFN), IFN-inducible genes and pro-inflammatory cytokines which skew the differentiation of monocytes toward pro-inflammatory macrophages (M1-like, Figure 1A). We investigated a homeostatic relationship between C1q and HMGB1 and demonstrated a specific C1q-HMGB1 interaction in which C1q can create a tetra-molecular complex with LAIR-1, HMGB1 and RAGE, bringing these molecules together in lipid rafts (Figure 1B). This complex triggers monocytes to acquire an anti-inflammatory (M2-like) phenotype, upregulating the expression of CD163 and several anti-inflammatory molecules including Programmed Death-Ligand 1, Mer tyrosine-kinase and Interleukin-10. These anti-inflammatory macrophages fail to differentiate to dendritic cells, blocking the downstream adaptive immune response. These findings highlight the importance of developing novel mechanism-based therapeutics to target DAMP-mediated inflammation while preserving other protective immune responses.

 

 

Figure 1. Model showing how C1q utilizes a natural pathway to dampen inflammation.  (A) DNA/RNA associated HMGB1 is internalized and activates endosomal TLRs, leading to downstream activation of NF-κB to induce M1-like macrophages. (B) With high levels of HMGB1, C1q mediates differentiation of M2-like macrophages by cross-linking RAGE and LAIR-1 in lipid rafts to facilitate SHP-1 binding to LAIR-1 via phosphorylated ITIMs. Activated SHP-1 may suppress directly or indirectly the pathways downstream of RAGE activation.

 

Acknowledgments:

This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (K01AR065506 for M.S.; R01AR057084 for B.D.) and the National Institutes of Health (S10 RR033072-01 for Y. A-A). M.S. was a recipient of an Arthritis Foundation Fellowship.

 

Contact:

Betty Diamond, M.D.

Head, Center for Autoimmune and Musculoskeletal Disease

The Feinstein Institute for Medical Research, North Shore – LIJ Health System

350 Community Drive, Manhasset, New York 11030

Tel:  516.562.38930; Fax: 516.562.2921

Email: bdiamond@northwell.edu

 

References

1. Son M, Santiago-Schwarz F, Al-Abed Y, Diamond B. C1q limits dendritic cell differentiation and activation by engaging LAIR-1. Proc Natl Acad Sci U S A. 2012;109(46):E3160-7. PubMed PMID: 23093673; PMCID: 3503216.

2. Son M, Diamond B. C1q-mediated repression of human monocytes is regulated by leukocyte-associated Ig-like receptor 1 (LAIR-1). Mol Med. 2014;20:559-68. PubMed PMID: 25247291; PMCID: 4365071.

3. Son M, Porat A, He M, Suurmond J, Santiago-Schwarz F, Andersson U, Coleman TR, Volpe BT, Tracey KJ, Al-Abed Y, Diamond B. C1q and HMGB1 reciprocally regulate human macrophage polarization. Blood. 2016;128(18):2218-28. PubMed PMID: 27683415; PMCID: PMC5095756.

4. Andersson U, Tracey KJ. HMGB1 is a therapeutic target for sterile inflammation and infection. Annual review of immunology. 2011;29:139-62. PubMed PMID: 21219181; PMCID: 4536551.