IL-1α and IL-36 Family Cytokines Can Undergo Processing and Activation by Diverse Allergen-Associated Proteases

Abstract

Inflammation driven by environmental allergens is an important source of morbidity in diseases such as asthma and eczema. How common allergens promote inflammation is still poorly understood, but previous studies have implicated the protease activity associated with many allergens as an important component of the pro-inflammatory properties of these agents. The IL-1 family cytokine, IL-33, has recently been shown to undergo processing and activation by proteases associated with multiple common allergens. However, it remains unclear whether the sensing of exogenous protease activity—as a proxy for the detection of invasive microbes, allergens and parasitic worms—is a general property of IL-1 family cytokines. In common with the majority of IL-1 family members, cytokines within the IL-36 sub-family (IL-36α, IL-36β and IL-36γ) are expressed as inactive precursors that require proteolysis within their N-termini for activation. Here we show that proteases associated with multiple common allergens of plant, insect, fungal and bacterial origin (including: Aspergillus fumigatus, ragweed, rye, house dust mite, cockroach and Bacillus licheniformis) are capable of processing and activating IL-36 family cytokines, with IL-36β being particularly susceptible to activation by multiple allergens. Furthermore, extracts from several allergens also processed and enhanced IL-1α activity. This suggests that multiple IL-1 family cytokines may serve as sentinels for exogenous proteases, coupling detection of such activity to unleashing the pro-inflammatory activity of these cytokines. Taken together with previous data on the diversity of proteases capable of activating IL-1 family cytokines, this suggests that members of this cytokine family may function as ‘activity recognition receptors’ for aberrant protease activity associated with infection, tissue injury or programmed necrosis.

Myeloid cell–derived proteases produce a proinflammatory form of IL-37 that signals via IL-36 receptor engagement

“…The predominant Cat S cleavage sites within IL-37 were mapped to His 47 and Val 52 , distinct from but in very close proximity to the elastase cleavage sites. This is suggestive of a “sensor domain” within the N terminus of IL-37 that is highly sensitive to proteolysis by divergent proteases, similar to what has been found with IL-1α, IL-33, and IL-36 subfamily cytokines ( 18 , 25 , 26 , 28 – 30 ). Thus, the identity of the specific proteases, as well as their concentration, encountered by IL-37 at inflammatory sites may have a major bearing on the activity of this cytokine, with Cat S serving in a predominantly activating capacity.…”

“…In contrast, although elastase can activate IL-37 at low nanomolar concentrations, this protease may suppress IL-37 activity at concentrations beyond this. Several IL-1 family cytokines are also capable of becoming processed and activated by exogenous pathogen-derived proteases, which could also be true for IL-37 but was not tested in the present study ( 25 , 27 – 30 ).…”

“…A large body of evidence has now accumulated to suggest that members of the extended IL-1 cytokine family serve as sentinels for diverse proteases that are either liberated into the extracellular space by activated innate immune cells, such as neutrophils or mast cells, or activated intracellularly in response to infection or tissue damage ( 10 , 12 , 14 , 18 – 20 , 25 , 26 ). Furthermore, accumulating evidence also suggests that IL-1 family cytokines are responsive to pathogen- as well as allergen-derived proteases ( 27 – 30 ) and appear to serve as “activity recognition receptors” for exogenous proteases or aberrant protease activity associated with infection [reviewed in ( 25 )]. Thus, the N-terminal pro-peptides of IL-1 family cytokines function as sensors for protease activity associated with pathogens, activated immune cells, or homeostatic perturbations that result in inflammasome activation.…”

“…It is interesting to contemplate why four members of the IL-1 family—IL-36α, IL-36β, IL-36γ, and IL-37—can all signal via the IL-36R. One possibility is that because of the diversity of pathogens encountered at the skin barrier, a site where IL-36R–dependent activity appears to dominate, several duplications of IL-36 family cytokines have occurred to enable each member of this family to evolve distinct N termini capable of responding to different pathogen proteases ( 25 , 29 , 30 ). Another possibility is that IL-37 has retained the ability to bind the IL-36R but has also acquired other properties, such as the ability to bind the IL-18R and IL-1R8/SIGIRR, thereby acquiring additional anti-inflammatory properties.…”

Protease allergens as initiators–regulators of allergic inflammation

“…182 Of note, besides IL-33 other alarmins belonging to the IL-1 family similarly contain a protease sensor domain which could be cleaved by protease allergens, as recently evidenced for IL-1α and IL-36. 183 The mechanism of allergen sensing by RipIL-33 deserves attention. The elucidation of the mechanism by which nociceptive neurons sense cysteine protease allergens directly (papain, HDM) is essential to our understanding of the neuron-immune interactions in allergic diseases.…”