The hypoxic tissue microenvironment as a driver of mucosal inflammatory resolution

Abstract

On the backdrop of all acute inflammatory processes lies the activation of the resolution response. Recent years have witnessed an emerging interest in defining molecular factors that influence the resolution of inflammation. A keystone feature of the mucosal inflammatory microenvironment is hypoxia. The gastrointestinal tract, particularly the colon, exists in a state of physiological hypoxia and during active inflammation, this hypoxic state is enhanced as a result of infiltrating leukocyte oxygen consumption and the activation of oxygen consuming enzymes. Most evidence suggests that mucosal hypoxia promotes the active resolution of inflammation through a variety of mechanisms, including extracellular acidification, purine biosynthesis/salvage, the generation of specialized pro-resolving lipid mediators (ie. resolvins) and altered chemokine/cytokine expression. It is now appreciated that infiltrating innate immune cells (neutrophils, eosinophils, macrophages) have an important role in molding the tissue microenvironment to program an active resolution response. Structural or functional dysregulation of this inflammatory microenvironment can result in the loss of tissue homeostasis and ultimately progression toward chronicity. In this review, we will discuss how inflammatory hypoxia drives mucosal inflammatory resolution and its impact on other microenvironmental factors that influence resolution.

A new microphysiological system shows hypoxia primes human ISCs for interleukin-dependent rescue of stem cell activity

“…8,12 Consistent with this concept, inflammatory responses have been shown to produce localized and chronic hypoxic episodes in the intestinal stem cell (ISC) zone, potentially leading to impaired ISC survival, renewal, and differentiation, ultimately impeding mucosal repair and producing ISC death. 6,15,16 While numerous studies focus on the impact of hypoxia on repair mechanisms involving restitution in differentiated entrocytes 6,[17][18][19][20][21] few studies investigate the impact of hypoxia on ISC properties and ISC-dependent repair mechanisms 22 , especially in human tissues. Traditionally, human cancer cell lines are used to study acute and chronic hypoxia at the cellular level but transformed cells exhibit abnormal proliferation and cell death dynamics and they do not properly differentiate, thus they are poor models of human ISCs (hISCs).…”

Editorial: Hypoxia and inflammation: A two-way street

“…In vitro experiments using peripheral blood-derived mononuclear cells (PMBCs) cultured under hypoxic conditions (9% O 2 , 16 hours) confirm this enhanced expression of CD39 on T and NK cells, while decreased expression of CD73 is observed. CD73 is responsible for the final degradation of adenosine triphosphate and diphosphate into the immunosuppressive adenosine ( 2 ). Accumulation of these two adenosine nucleotides resulting from altered CD73 expression stimulates purinergic receptors expressed by platelets and monocytes.…”

“…EPO pathway increases apoptotic neutrophil elimination (the efferocytosis process) promoting the resolution phase of inflammation ( 10 ). Efferocytosis is critical, since neutrophils play a major role in depleting local oxygen in inflamed tissue ( 2 ). Chronic hypoxia increases efferocytic capacities of both murine and human macrophages ( 11 , 12 ).…”

“…Chronic hypoxia increases efferocytic capacities of both murine and human macrophages ( 11 , 12 ). Thus, hypoxia could also promote inflammation resolution ( 2 ).…”

Hypoxia Primes Human ISCs for Interleukin-Dependent Rescue of Stem Cell Activity

“… 8 , 12 Consistent with this concept, inflammatory responses have been shown to produce localized and chronic hypoxic episodes in the intestinal stem cell (ISC) zone, potentially leading to impaired ISC survival, renewal, and differentiation, ultimately impeding mucosal repair and producing ISC death. 6 , 15 , 16 …”