C1q and HMGB1 reciprocally regulate human macrophage polarization

Son, Myoungsun; Porat, Amit; He, Mingzhu; Suurmond, Jolien; Santiago‐Schwarz, Frances; Andersson, Ulf; Coleman, Thomas R.; Volpe, Bruce T.; Tracey, Kevin J.; Al‐Abed, Yousef; Diamond, Betty

doi:10.1182/blood-2016-05-719757

Cited by 133 publications

(126 citation statements)

References 61 publications

(69 reference statements)

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“…Unlike the immediate signal for enhanced phagocytosis which is mediated by the collagen-like tails of C1q, and conserved with MBL, programmed efferocytosis required the full-length C1q molecule and was not shared with MBL. While primary human macrophages failed to upregulate Mer expression following prolonged stimulation with C1q alone (Hulsebus et al, 2016), human monocytes and dendritic cells cultured with the combination of C1q and HMGB1 upregulated Mer, suggesting with a conserved pathway in mouse and human cells (Son et al, 2016). These data are consistent with the observation that there is a reduction in the expression of pro-engulfment genes in macrophages from patients with SLE (Majai et al, 2014).…”

Section: Classical Functions: Complement Phagocytosis and Cytokinmentioning

confidence: 99%

“…LAIR-1 engagement by C1q inhibits DC differentiation and activation either during steady state or inflammation and is suggested to help maintain monocyte tolerance (Son et al, 2012; Son and Diamond, 2015). In addition, C1q was reported recently to suppress the HMGB1-polarization of monocytes and maintain an anti-inflammatory M2-like macrophage, a pathway mediated through a complex with both RAGE and LAIR-1 and depending on the relative levels of C1q and HMGB1 (Son et al, 2016). …”

Section: Interaction With Cell Surface Proteins: Old and New Recepmentioning

confidence: 99%

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C1q: A fresh look upon an old molecule

Thielens

Tedesco

Bohlson

et al. 2017

Molecular Immunology

182

139

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Originally discovered as part of C1, the initiation component of the classical complement pathway, it is now appreciated that C1q regulates a variety of cellular processes independent of complement activation. C1q is a complex glycoprotein assembled from 18 polypeptide chains, with a C-terminal globular head region that mediates recognition of diverse molecular structures, and an N-terminal collagen-like tail that mediates immune effector mechanisms. C1q mediates a variety of immunoregulatory functions considered important in the prevention of autoimmunity such as the enhancement of phagocytosis, regulation of cytokine production by antigen presenting cells, and subsequent alteration in T-lymphocyte maturation. Furthermore, recent advances indicate additional roles for C1q in diverse physiologic and pathologic processes including pregnancy, tissue repair, and cancer. Finally, C1q is emerging as a critical component of neuronal network refinement and homeostatic regulation within the central nervous system. This review summarizes the classical functions of C1q and reviews novel discoveries within the field.

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Section: Classical Functions: Complement Phagocytosis and Cytokinmentioning

confidence: 99%

Section: Interaction With Cell Surface Proteins: Old and New Recepmentioning

confidence: 99%

C1q: A fresh look upon an old molecule

Thielens

Tedesco

Bohlson

et al. 2017

Molecular Immunology

182

139

View full text Add to dashboard Cite

show abstract

“…A previous study demonstrated that C1q inhibits the proin ammatory effects of HMGB1 on monocytes 45 .…”

Section: Resultsmentioning

confidence: 97%

Neuronal NR4A1 and complement coordinate synaptic stripping by microglia in lupus

Han¹,

Xu²,

Fang³

et al. 2020

Preprint

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Up to 75% of systematic lupus erythematosus (SLE) patients experience neuropsychiatric (NP) symptoms, called neuropsychiatric SLE (NPSLE), yet the underlying mechanisms remain elusive. Here we showed that complement-coordinated elimination of synapses participated in NPSLE in MRL/lpr mice, a lupus-prone murine model. We demonstrated that lupus mice developed increased anxiety-like behaviors and persistent phagocytic microglia reactivation before overt peripheral lupus pathology. In lupus brain, C1q was increased and localized at synaptic terminals, causing the apposition of phagocytic microglia, ensuing synaptic loss, and neurological disease. We further determined that neuronal Nr4a1 signaling was essential for attracting C1q synaptic deposition and then apposition of phagocytic microglia, resulting in synaptic loss and neurological disease. Minocycline-deactivated microglia, antibody-blocked C1q, or neuronal Nr4a1 restored protected lupus mice from synapse loss and NP manifestations. Our findings revealed an active role of neurons in coordinating microglia-mediated synaptic loss and highlight neuronal Nr4a1 and C1q as critical components amenable to pharmacological intervention in NPSLE.

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“…The proinflammatory activity of HMGB1 is well studied. However, the anti-inflammatory activity of HMGB1 also has been documented in multiple studies (49)(50)(51). Recently, it was shown that HMGB1 binds soluble CD52 and this complex binds with Siglec-10 on T-cells leading to SHP-1 (phosphatase) recruitment that dephosphorylates LCK and Zap70, thus activating an anti-inflammatory cascade (26,52).…”

Section: Discussionmentioning

confidence: 97%

Acidosis, Zinc and HMGB1 in Sepsis: A Common Connection Involving Sialoglycan Recognition

Siddiqui

Dhar

Sundaramurthy

et al. 2020

Preprint

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Blood pH is tightly regulated between 7.35-7.45, with values below 7.3 during sepsis being associated with lactic acidosis, low serum zinc, and release of proinflammatory HMGB1 from activated and/or necrotic cells. Using an ex vivo whole blood system to model lactic acidosis, we show that while HMGB1 does not engage leukocyte receptors at physiological pH, lowering pH with lactic acid facilitates binding. At normal pH, micromolar zinc supports plasma sialoglycoprotein binding by HMGB1, which is markedly reduced when pH is adjusted with lactic acid to sepsis levels. Glycan array studies confirmed zinc and pH-dependent HMGB1 binding to sialoglycans typical of plasma glycoproteins. Thus, proinflammatory effects of HMGB1 are suppressed via plasma sialoglycoproteins until drops in pH and zinc release HMGB1 to trigger downstream immune activation.Significance StatementHMGB1 sequestered by plasma sialoglycoproteins at physiological pH is released when pH and zinc concentrations fall in sepsis.

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C1q and HMGB1 reciprocally regulate human macrophage polarization

Abstract: Key Points C1q can form a multimolecular signaling complex with HMGB1, RAGE, and LAIR-1 in lipid rafts. C1q and HMGB1 together promote monocytes to differentiate to an anti-inflammatory phenotype.

Cited by 133 publications

References 61 publications

C1q: A fresh look upon an old molecule

C1q: A fresh look upon an old molecule

Neuronal NR4A1 and complement coordinate synaptic stripping by microglia in lupus

Acidosis, Zinc and HMGB1 in Sepsis: A Common Connection Involving Sialoglycan Recognition

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