Monocyte-lymphocyte cross-communication via soluble CD163 directly links innate immune system activation and adaptive immune system suppression following ischemic stroke

Abstract

CD163 is a scavenger receptor expressed on innate immune cell populations which can be shed from the plasma membrane via the metalloprotease ADAM17 to generate a soluble peptide with lympho-inhibitory properties. The purpose of this study was to investigate CD163 as a possible effector of stroke-induced adaptive immune system suppression. Liquid biopsies were collected from ischemic stroke patients (n = 39), neurologically asymptomatic controls (n = 20), and stroke mimics (n = 20) within 24 hours of symptom onset. Peripheral blood ADAM17 activity and soluble CD163 levels were elevated in stroke patients relative to non-stroke control groups, and negatively associated with post-stroke lymphocyte counts. Subsequent in vitro experiments suggested that this stroke-induced elevation in circulating soluble CD163 likely originates from activated monocytic cells, as serum from stroke patients stimulated ADAM17-dependant CD163 shedding from healthy donor-derived monocytes. Additional in vitro experiments demonstrated that stroke-induced elevations in circulating soluble CD163 can elicit direct suppressive effects on the adaptive immune system, as serum from stroke patients inhibited the proliferation of healthy donor-derived lymphocytes, an effect which was attenuated following serum CD163 depletion. Collectively, these observations provide novel evidence that the innate immune system employs protective mechanisms aimed at mitigating the risk of post-stroke autoimmune complications driven by adaptive immune system overactivation, and that CD163 is key mediator of this phenomenon.

CD163 and pAPN double-knockout pigs are resistant to PRRSV and TGEV and exhibit decreased susceptibility to PDCoV while maintaining normal production performance

“…Additionally, the effect of CD163 knockout in the delayed adaptive immune response cannot be ignored. Despite the important role of CD163 in innate immunity, an inhibiting effect of soluble CD163 on the adaptive immune system has also been reported ( Frings et al, 2002 ; O'Connell et al, 2017 ). It is thus possible that the delayed adaptive immune response we observed in PDCoV-infected DKO pigs may be associated with CD163 knockout-induced immunosuppression.…”

MicroRNA networks associated with active systemic juvenile idiopathic arthritis regulate CD163 expression and anti-inflammatory functions in macrophages through two distinct mechanisms

“…In turn, CD163‐expressing monocytes and macrophages serve key roles during inflammation by clearing damaging substrates such as Hgb and HMGB1 and producing anti‐inflammatory mediators. Indeed, CD163 expression reduces mortality in a mouse model of sepsis, and sCD163 has suppressive effects on lymphocytes in vitro . MicroRNAs are increasingly recognized as having key roles in regulating functional polarization of monocytes and macrophages.…”

RNA sequencing reveals novel macrophage transcriptome favoring neurovascular plasticity after ischemic stroke

“…For example, monocytes contribute to post-stroke immunodepression by suppressing lymphocyte activity through soluble factors, such as CD163 and CD14. 48 We did not detect dramatic transcriptomic changes in blood monocytes following ischemic stroke (only 127 DEGs). Furthermore, this mild genomic change did not support an activation or inhibition state for these cells nor did these cells acquire conventional polarization phenotypes.…”