Microbiota Composition and the Integration of Exogenous and Endogenous Signals in Reactive Nasal Inflammation

Abstract

The prevalence of reactive nasal inflammatory conditions, for example, allergic rhinitis and chronic rhinosinusitis, is steadily increasing in parallel with significant environmental changes worldwide. Allergens and as yet undefined environmental agents may trigger these conditions via the involvement of host intrinsic factors, including the innate and adaptive immune system, the nasal epithelium, and the nasal nervous system. The critical role of the nasal microbiota in coordinating these components has emerged in recent studies documenting a significant association between microbial composition and the onset and progression of allergic or nonallergic inflammation. It is now clear that the local microbiota is a major player in the development of the mucosa-associated lymphoid tissue and in the regulation of such adaptive responses as IgA production and the function of effector and regulatory T cells. Microbial components also play a major role in the regulation of epithelial barrier functions, including mucus production and the control of paracellular transport across tight junctions. Bacterial components, including lipopolysaccharide, have also been shown to induce or amplify neuroinflammatory responses by engaging specific nociceptors. Finally, bacterial products may promote tissue remodeling processes, including nasal polyp formation, by interacting with formyl peptide receptors and inducing the expression of angiogenic factors and matrix-degrading enzymes.

Figure 1

The regulation of immune responses by microbiota-associated factors. Follicular dendritic cells (FDC), myeloid differentiation primary response 88 (MyD88)⁺ phagocytes, and ROR-γt⁺ ILC are stimulated by commensal bacteria to produce cytokines and other proinflammatory mediators. These responses involve, among other outcomes, the secretion of dimeric IgA, mucus, and antimicrobial peptides and are critically regulated by FoxP3⁺ Treg cells (see text).

Figure 2

The relationship of allergen-induced, type 2 immune responses and the nasal nervous system. Trigeminal fibers are responsible for tactile sensitivity, including nociception, and release such neuropeptides as substance P, neurokinin A, CGPR, and possibly NMU (see text). These mediators induce vasodilation and directly activate cytotypes involved in the inflammatory response, for example, mast cells, eosinophils, lymphocytes, and macrophages. Parasympathetic postganglionic fibers release acetylcholine and induce vasodilation and mucus production, while norepinephrine from sympathetic fibers may induce vasoconstriction by interacting with α-adrenergic receptors, which typically prevails over vasodilation induced by concomitant ligation of β-receptors.

Figure 3

The effect of corticosteroid treatment on eosinophilic inflammation in CRSwNP. Hematoxylin and eosin stainings of polyp sections from two patients with CRSwNP before (a and c) and after (b and d) a short course of oral prednisone (0.4 mg/kg/day for 7 days) prior to polyp resection by functional endoscopic sinus surgery. Both patients did not have any allergies and were aspirin-intolerant. Polyp size and eosinophilic infiltration in the first patient (a and b), a 50-year-old female, were promptly reduced following prednisone administration, whereas polyp size and histology in the second patient (c and d), a 69-year-old male, remained substantially unchanged (F.A. Salzano and C. Stellato, unpublished observations).