Biology subjects

Souza, D. G.

Publications and source records attributed to Souza, D. G..

3 recordsLinked to original sources

bioRxiv2024

Activation of bradykinin receptor B1 promotes desensitization of CXCR2 in neutrophils during severe sepsis and contributes to disease progression in mice.

Sepsis is one of the most common causes of death in intensive care units. The overproduction of proinflammatory mediators during severe sepsis leads to desensitization of CXCR2 on neutrophil, compromising their migration capacity. During early sepsis, kinins are released and bind to bradykinin 1 (BDKRB1) and bradykinin 2 (BDKRB2) receptors, however the involvement of these receptors in sepsis is not yet fully understood. This study demonstrated that the absence of BDKRB2 had no major effects compared to WT mice upon sepsis induction by CLP, suggesting that this receptor plays a minor role under these experimental conditions. In contrast, B1-/- mice showed lower mortality and bacterial recovery compared to WT-CLP mice, which was associated with an increased influx of neutrophils into the peritoneal cavity of CLP-B1-/- mice. WT-CLP mice exhibited increased expression of P110{gamma} and decreased expression of CXCR2 in neutrophils, which was partially reversed in CLP-B1-/- mice. Interestingly, local CXCL1 production was not affected by the absence of BDKRB1. In human neutrophils, LPS induced expression of BDKRB1, and antagonism of this receptor was associated with the restoration of neutrophil recruitment capacity upon stimulation with CXCL8. Furthermore, treatment with a BDKRB1 antagonist in combination with imipenem resulted in a significant improvement in mortality compared to animals treated with the antimicrobial agent alone. Our findings demonstrate that BDKRB1 plays an essential role in exacerbating the inflammatory response and CXCR2 desensitization in neutrophils during CLP-induced severe sepsis, highlighting BDKRB1 as a potential target for sepsis treatment. ImportanceSepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Despite advances in understanding its pathophysiology, sepsis remains a leading cause of mortality in intensive care units nowadays. Here we found that B1 receptor contributes to neutrophil migration failure during severe sepsis. Inhibition of B1 improves neutrophil migration and bacterial clearance, making it a valuable therapeutic candidate for the treatment of sepsis. More importantly, treatment with a BDKRB1 antagonist in combination with imipenem resulted in a significant improvement in mortality compared to animals treated with the antimicrobial agent alone. These results highlight B1 as a potential treatment target for sepsis, offering improved modulation of the inflammatory response and synergy with antibiotics. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/590213v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1f0401aorg.highwire.dtl.DTLVardef@ab8eorg.highwire.dtl.DTLVardef@1ff0c26org.highwire.dtl.DTLVardef@176b5aa_HPS_FORMAT_FIGEXP M_FIG BDKRB1 activation contributes to sepsis-induced hyperinflammation: (A) BDKRB1 activation contributes to sepsis-induced hyperinflammation: (A) BDKRB1 plays an essential role in the pathogenesis of sepsis, partly by mediating impaired neutrophil migration during the disease. It exerts its effects in myeloid cells by controlling the activation of P13K{gamma} and the expression of CXCR2. (B) BDKRB1 antagonist decreases cytokine production and increases neutrophil influx into the peritoneal cavity, resulting in a reduction in bacterial recovery, highlighting DALBK as a potential adjuvant treatment for sepsis C_FIG

microbiology↗

bioRxiv2023

Essential role of the CCL2-CCR2 axis in Mayaro virus-induced disease

Mayaro virus (MAYV) is an emerging arbovirus member of the Togaviridae family and Alphavirus genus. MAYV infection causes an acute febrile illness accompanied by persistent polyarthralgia and myalgia. Understanding the mechanisms involved in arthritis caused by alphaviruses is necessary to develop specific therapies. In this work, we investigated the role of the CCL2/CCR2 axis in the pathogenesis of MAYV-induced disease. For this, WT C57BL/6J and CCR2-/- mice were infected with MAYV subcutaneously and evaluated for disease development. MAYV infection induced an acute inflammatory disease in WT mice. The immune response profile was characterized by an increase in the production of inflammatory mediators, such as IL-6, TNF and CCL2. Higher levels of CCL2 at the local and systemic levels, was followed by significant recruitment of CCR2+ macrophages and a cellular response orchestrated by these cells. CCR2-/- mice showed an increase in CXCL-1 levels, followed by a replacement of the macrophage inflammatory infiltrate by neutrophils. Additionally, absence of the CCR2 receptor protected mice from bone loss induced by MAYV. Accordingly, the silencing of CCL2 chemokine expression in vivo and the pharmacological blockade of CCR2 promoted a partial improvement in disease. Cell culture data support the mechanism underlying MAYVs bone pathology in which: i) MAYV infection promoted a pro-osteoclastogenic microenvironment mediated by IL-6, TNF and CCL2 and ii) migration of osteoclast precursors was dependent on the CCR2/CCL2 axis. Overall, these data contribute to the understanding of the pathophysiology of MAYV infection and to the identification future of specific therapeutic targets in MAYV-induced disease. ImportanceThis work demonstrates the role of the CCL2/CCR2 axis in MAYV-induced disease. Infection of WT C57BL/6J and CCR2-/- mice was associated with high levels of CCL2, an important chemoattractant involved in the recruitment of macrophages, the main precursor of osteoclasts. In the absence of the CCR2 receptor there is a mitigation of macrophage migration to the target organs of infection and protection of these mice against bone loss induced by MAYV infection. Much evidence has shown that host immune response factors contribute significantly to the tissue damage associated to alfavirus infections. Thus, this work highlights molecular and cellular targets involved in the pathogenesis of arthritis triggered by MAYV, and identifies novel therapeutic possibilities directed to the host inflammatory response unleashed by MAYV.

cell biology↗

bioRxiv2021

Targeting the Annexin A1-FPR2/ALX pathway for host-directed therapy in dengue disease

Host immune responses contribute to dengues pathogenesis and severity, yet the possibility that failure in endogenous inflammation resolution pathways could characterise the disease has not been contemplated. The pro-resolving protein Annexin A1 (AnxA1) is known to counterbalance overexuberant inflammation and mast cell (MC) activation. We hypothesised that inadequate AnxA1 engagement underlies the cytokine storm and vascular pathologies associated with dengue disease. Levels of AnxA1 were examined in the plasma of dengue patients and infected mice. Immunocompetent, IFN/{beta}R-/-, AnxA1-/- and FPR2/ALX-/- mice were infected with Dengue virus (DENV) and treated with the AnxA1 mimetic peptide Ac2-26 for analysis. Additionally, the effect of Ac2-26 on DENV-induced MC degranulation was assessed in vitro and in vivo. We observed that circulating levels of AnxA1 were reduced in dengue patients and DENV-infected mice. While the absence of AnxA1 or its receptor FPR2/ALX aggravated illness in infected mice, treatment with AnxA1 agonistic peptide attenuated disease manifestations. Both clinical outcomes were attributed to modulation of DENV-mediated viral load-independent MC degranulation. We have thereby identified that altered levels of the pro-resolving mediator AnxA1 are of pathological relevance in DENV infection, suggesting FPR2/ALX agonists as a therapeutic target for dengue disease.

microbiology↗