The Impact of Neutrophil Recruitment to the Skin on the Pathology Induced by Leishmania Infection

Abstract

Leishmania (L.) are obligate intracellular protozoan parasites that cause the leishmaniases, a spectrum of neglected infectious vector-borne diseases with a broad range of clinical manifestations ranging from local cutaneous, to visceral forms of the diseases. The parasites are deposited in the mammalian skin during the blood meal of an infected female phlebotomine sand fly. The skin is a complex organ acting as the first line of physical and immune defense against pathogens. Insults to skin integrity, such as that occurring during insect feeding, induces the local secretion of pro-inflammatory molecules generating the rapid recruitment of neutrophils. At the site of infection, skin keratinocytes play a first role in host defense contributing to the recruitment of inflammatory cells to the infected dermis, of which neutrophils are the first recruited cells. Although neutrophils efficiently kill various pathogens including Leishmania, several Leishmania species have developed mechanisms to survive in these cells. In addition, through their rapid release of cytokines, neutrophils modulate the skin microenvironment at the site of infection, a process shaping the subsequent development of the adaptive immune response. Neutrophils may also be recruited later on in unhealing forms of cutaneous leishmaniasis and to the spleen and liver in visceral forms of the disease. Here, we will review the mechanisms involved in neutrophil recruitment to the skin following Leishmania infection focusing on the role of keratinocytes in this process. We will also discuss the distinct involvement of neutrophils in the outcome of leishmaniasis.

Neutrophil Activation: Influence of Antimony Tolerant and Susceptible Clinical Strains of L. (V.) panamensis and Meglumine Antimoniate

“…However, the importance of the host cell in determining susceptibility is illustrated by the distinct EC 50 of antileishmanial drugs for the same parasite in different host cells (primary macrophages or mononuclear phagocytic cell lines ( Seifert et al., 2010 )), and the divergence of drug screening results based on intracellular amastigotes, promastigotes, and axenic amastigotes ( Vermeersch et al., 2009 ; De Muylder et al., 2011 ; Zahid et al., 2019 ). Furthermore, growing evidence indicates that neutrophils, the first host cells recruited to the site of infection, may play a role in the pathogenesis of leishmaniasis depending on the infecting Leishmania spp ( Afonso et al., 2008 ; Carlsen et al., 2013 ; Hurrell et al., 2015 ; Charmoy et al., 2016 ; Hurrell et al., 2016 ; Passelli et al., 2021 ). Despite their important role in cutaneous leishmaniasis, the involvement of neutrophils in the response to antileishmanial drugs has not been examined.…”

“…Previous studies have shown that elimination or survival of Leishmania parasites by or within neutrophils differs among parasite species or even strains of the same species ( Hurrell et al., 2016 ; Regli et al., 2017 ). Leishmania may be killed or inhibit the otherwise very efficient killing machinery of these cells ( Passelli et al., 2021 ) and effectively mediate the transfer of parasites to macrophages ( van Zandbergen et al., 2004 ; Chaves et al., 2020 ). Infection of human neutrophils with laboratory-derived MIL and SbV resistant lines of L. (V.) panamensis elicited significantly greater NET formation by both murine and human neutrophils compared to infections with the wild-type (WT) sensitive line, while the MIL resistant line, but not SbV resistant line, also elicited significantly higher ROS production than SbV resistant or sensitive lines ( Regli et al., 2018 ).…”

Bifidobacterium Longum: Protection against Inflammatory Bowel Disease

“…For example, Th1 cells can secrete tumor necrosis factor α (TNF-α) to initiate a variety of proinflammatory responses [53]. Th17 cells are involved in the activation and recruitment of neutrophils [54]. Treg cells can express the transcription factor forkhead box P3 (FOXP3) and secrete the anti-inflammatory cytokine IL-10, thereby inhibiting a strong inflammatory response [55].…”

The Immune System Throws Its Traps: Cells and Their Extracellular Traps in Disease and Protection

“…from the early stages of infection, as they are rapidly recruited into the skin after the entry of the protozoan. Interestingly, it has already been demonstrated that the saliva of Lutzomyia longipalpis, one of the insects that transmit this parasite, has endonucleases capable of degrading NETs, which could indirectly act on the pathogenesis of the disease [64,[67][68][69][70]. In addition, NETs are also observed in ATL lesions presenting different evolution times, suggesting a continuous role of neutrophils in tissue inflammation [29].…”