Neutrophils are gatekeepers of mucosal immunity

Abstract

Mucosal tissues are constantly exposed to the outside environment. They receive signals from the commensal microbiome and tissue-specific triggers including alimentary and airborne elements and are tasked to maintain balance in the absence of inflammation and infection. Here, we present neutrophils as sentinel cells in mucosal immunity. We discuss the roles of neutrophils in mucosal homeostasis and overview clinical susceptibilities in patients with neutrophil defects. Finally, we present concepts related to specification of neutrophil responses within specific mucosal tissue microenvironments.

Keywords: gastrointestinal; lung; mucosal immunity; neutropenia; neutrophils; oral.

Figure 1.. Neutrophil functions are essential for mucosal immunity.

Neutrophil functions are critical for mucosal barrier defense. Anti-microbial functions of neutrophils are essential during infection. Wound clearance through phagocytosis is key during injury but also for homeostatic tissue repair. Resolution of inflammation is necessary to promote healing and repair and for constant regulation of inflammatory reactions at the barrier.

Figure 2.. Neutrophil heterogeneity in respiratory tract.

Developmentally divergent neutrophils (Neu) have been detected in the circulation and respiratory tract mucosa during inflammatory conditions. Lungs contain a marginated intravascular pool of neutrophils with tissue-specific marker expression. Additionally, immature neutrophils and low-density neutrophils (LDNs) have been identified in the respiratory mucosa during disease states. Furthermore, select neutrophil subtypes have been identified in distinct infections. These subsets may exert various effector functions with different capabilities. C-C motif chemokine ligand (CCL); C-C motif chemokine receptor (CCR); cysteinyl leukotriene receptor 1 (CysLTR1); C-X-C chemokine receptors (CXCR); forward scatter (FSC); interferon receptor (IFNR); interleukin (IL); neutrophil extracellular trap formation (NETosis); reactive oxygen species (ROS); S100 calcium binding protein A (S100A); severe fever with thrombocytopenia syndrome (SFTS); tumor necrosis factor (TNF)

Figure 3.. Neutrophil function and heterogeneity in oral mucosa.

The gingival crevice, the epithelium of the periodontal pocket, is a site of constant transmigration of neutrophils even in health. Neutrophils constantly transmigrate from the vasculature to the gingival tissue and through the bottom of the pocket into the oral cavity. This tissue has a great extent of homeostatic inflammation that is primarily characterized by neutrophil responses. Neutrophils transmigrating into the oral cavity have been subclassified into two populations of health-associated para-inflammatory neutrophils (P1 and P2) and a proinflammatory subtype (P3) in periodontitis. Oral neutrophils express CD11b, CD16, CD66 and varying levels of CD10, CD18, CD55, CD63, CD64, and CD170. P3 neutrophils in particularly are characterized by increased expression of activation markers and increased propensity towards ROS production and NETosis.

Figure 4.. Cross regulation of the microbiome with neutrophils at the gastrointestinal mucosa.

At the GI tract, microbiota play a key role in the regulation of neutrophil responses. Commensal microbiota generally engages immunoregulatory responses which inhibit excessive neutrophil infiltration. Pathogenic microbiota trigger neutrophil recruitment and activation at the GI tract. Neutrophils recruited by pathogens can exit into the lumen to mediate protection to the host. However, many pathogens have found ways to use neutrophil responses for their growth advantage and thus perpetuate neutrophil infiltration and activation for their benefit.