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Differential and sequential immunomodulatory role of neutrophils and Ly6C^hi inflammatory monocytes during antiviral antibody therapy.

ABSTRACT: Antiviral monoclonal antibodies (mAbs) can generate protective immunity through Fc-FcγRs interactions. We previously showed a role for immune complexes (ICs) in the enhancement of antiviral T-cell responses through FcγR-mediated activation of dendritic cells (DCs). Here we addressed how mAb therapy in retrovirus-infected mice affects the activation of neutrophils and inflammatory monocytes, two FcγR-expressing innate effector cells rapidly recruited to sites of infection. We found that both cell-types activated in vitro by viral ICs secreted chemokines able to recruit monocytes and neutrophils themselves. Moreover, inflammatory cytokines potentiated chemokines and cytokines release by IC-activated cells and induced FcγRIV upregulation. Similarly, infection and mAb-treatment upregulated FcγRIV on neutrophils and inflammatory monocytes and enhanced their cytokines/chemokines secretion. Notably, upon antibody therapy neutrophils and inflammatory monocytes displayed distinct functional activation states and sequentially modulated the antiviral immune response by secreting Th1-type polarizing cytokines and chemokines, which occurred in a FcγRIV-dependent manner. Consistently, FcγRIV- blocking in mAb-treated, infected mice led to reduced immune protection. Our work provides new findings on the immunomodulatory role of neutrophils and monocytes in the enhancement of immune responses upon antiviral mAb therapy.

SUBMITTER: Lambour J

PROVIDER: S-EPMC8158214 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Heme oxygenase-1 (Hmox1) is a stress-inducible protein crucial in heme catabolism. The end products of its enzymatic activity possess anti-oxidative, anti-apoptotic and anti-inflammatory properties. Cardioprotective effects of Hmox1 were demonstrated in experimental models of myocardial infarction (MI). Nevertheless, its importance in timely resolution of post-ischemic inflammation remains incompletely understood. The aim of this study was to determine the role of Hmox1 in the monocyte/macrophage-mediated cardiac remodeling in a mouse model of MI. Hmox1 knockout (Hmox1-/-) and wild-type (WT, Hmox1+/+) mice were subjected to a permanent ligation of the left anterior descending coronary artery. Significantly lower incidence of left ventricle (LV) free wall rupture was noted between 3rd and 5th day after MI in Hmox1-/- mice resulting in their better overall survival. Then, starting from 7th until 21st day post-MI a more potent deterioration of LV function was observed in Hmox1-/- than in the surviving Hmox1+/+ mice. This was accompanied by higher numbers of Ly6Chi monocytes in peripheral blood, as well as higher expression of monocyte chemoattractant protein-1 and adhesion molecules in the hearts of MI-operated Hmox1-/- mice. Consequently, a greater post-MI monocyte-derived myocardial macrophage infiltration was noted in Hmox1-deficient individuals. Splenectomy decreased the numbers of circulating inflammatory Ly6Chi monocytes in blood, reduced the numbers of proinflammatory cardiac macrophages and significantly improved the post-MI LV function in Hmox1-/- mice. In conclusion, Hmox1 deficiency has divergent consequences in MI. On the one hand, it improves early post-MI survival by decreasing the occurrence of cardiac rupture. Afterwards, however, the hearts of Hmox1-deficient mice undergo adverse late LV remodeling due to overactive and prolonged post-ischemic inflammatory response. We identified spleen as an important source of these cardiovascular complications in Hmox1-/- mice.

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Differential and sequential immunomodulatory role of neutrophils and Ly6Chi inflammatory monocytes during antiviral antibody therapy.

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Differential and sequential immunomodulatory role of neutrophils and Ly6C^hi inflammatory monocytes during antiviral antibody therapy.