Aedes aegypti saliva impairs M1-associated proinflammatory phenotype without promoting or affecting M2 polarization of murine macrophages

Abstract

Background During the feeding process, the mouthparts of hematophagous mosquitoes break the skin barrier and probe the host tissue to find the blood. The saliva inoculated in this microenvironment modulates host hemostasis, inflammation and adaptive immune responses. However, the mechanisms involved in these biological activities remain poorly understood and few studies explored the potential roles of mosquito saliva on the individual cellular components of the immune system. Here, we report the immunomodulatory activities of Aedes aegypti salivary cocktail on murine peritoneal macrophages. Results The salivary gland extract (SGE) of Ae. aegypti inhibited the production of nitric oxide and inflammatory cytokines such as interleukin-6 (IL-6) and IL-12, as well as the expression of inducible nitric oxide synthase and NF-κB by murine macrophages stimulated by lipopolysaccharide (LPS) plus interferon-γ (IFN-γ). The spare respiratory capacity, the phagocytic and microbicidal activities of these macrophages were also reduced by Ae. aegypti SGE. These phenotypic changes are consistent with SGE suppressing the proinflammatory program of M1 macrophages. On the other hand, Ae. aegypti SGE did not influence M2-associated markers (urea production, arginase-1 and mannose receptor-1 expression), either in macrophages alternatively activated by IL-4 or in those classically activated by LPS plus IFN-γ. In addition, Ae. aegypti SGE did not display any cytokine-binding activity, nor did it affect macrophage viability, thus excluding supposed experimental artifacts. Conclusions Given the importance of macrophages in a number of biological processes, our findings help to enlighten how vector saliva modulates vertebrate host immunity.

Aedes Mosquito Salivary Components and Their Effect on the Immune Response to Arboviruses

“…Suppressing the expression of iNOS lowers the levels of the reactive oxygen intermediate NO which is an important factor that regulates the functional activity, growth, and death of macrophages, T cells, NK cells, and neutrophils. Thus, the decrease of NO levels by mosquito saliva deregulates the activity of these immune cells (Schneider et al, 2010;Barros et al, 2019). Neutrophils are an abundant cell population of the innate immune system.…”

Evaluation of inflammatory skin infiltrate following Aedes aegypti bites in sensitized and non‐sensitized mice reveals saliva‐dependent and immune‐dependent phenotypes

“…An important aspect to be highlighted is that while some studies, such as the present one, evidence the proinflammatory nature of the salivary secretion, a number of other studies describe anti‐inflammatory activities of saliva, including some molecules associated to this phenotype . This apparent ambiguity concerning the comprehension of vector saliva properties at the skin level may reflect an evolutionary battlefield between the mosquito and the vertebrate host.…”

AeMOPE-1, a Novel Salivary Peptide From Aedes aegypti, Selectively Modulates Activation of Murine Macrophages and Ameliorates Experimental Colitis

“…In addition, the presence of syn-AeMOPE-1 in cultures of resting macrophage did not affect the basal levels of the parameters evaluated. Similarly, macrophage viability was monitored by flow cytometry and by a resazurin-based assay (21,34,44), and no evidence was found concerning AeMOPE-1 toxicity under these conditions. The literature on the activities of Ae.…”

“…A similar phenotype has been recently described when macrophages were incubated with Ae. aegypti SGE ( 20 , 21 ). Strikingly, the fractionation of the SGE confirmed that the active fractions containing low molecular weight molecules recognized by an immune serum raised against AeMOPE-1 were associated with the nitric oxide inhibition, strongly suggesting a similar biological effect of the naturally secreted peptide.…”

“…aegypti SGE produced less nitric oxide, IL-6 and IL-12 and more IL-10. This phenotype was associated with inhibition of iNOS and phosphorylated nuclear factor-κB (NF-κB) ( 21 ). Likewise, murine macrophages activated with LPS and incubated with cecropins (antimicrobial peptides identified in the Ae.…”