MD Biosciences Blog

The Pathology of the IL-33/T1/ST2 Pathway: Harmin’ Alarmin

Posted by MD Biosciences

on Aug 10, 2015 4:30:00 PM

IL-33 is a member of the IL-1 cytokine family that is expressed constitutively in the nucleus of epithelial and endothelial cells as well as in CNS oligodendrocyte and astrocyte cells (1-2). Its release in response to cell damage and/or death has earned it the classification of “alarmin” – an immunological alarm signal that is released in times of cellular distress (3-4). Upon release, IL-33 binds to the T1/ST2 and IL-1R accessory protein (IL-1RAP) heterodimer complex to activate the MYD88-dependant signaling pathway (1).

Studies targeting the function of IL-33 and/or signaling through its T1/ST2 receptor have highlighted the dual role this versatile cytokine pathway plays in the induction inflammatory immune reactions. More interestingly, these reactions can be either beneficial or pathological in nature. Here we will discuss the pathological role of IL-33 in disease.

 

Role of IL-22 in Pathology

The presence of IL-33 is not always desirable. In certain mouse models of skin (56) and nasal mucosal (6-7) allergy, IL-33 is necessary for the perpetuation of anti-allergen immunity. Animals deficient in IL-33 fail to respond or exhibit weak allergic reactions (8). Increases in signaling through the IL-33 via enrichment of its T1/ST2 receptor has been shown to occur in both the nasal polyps of human chronic rhinosinusitis patients (9) and in lesional skin biopsies of patients with atopic dermatitis, where increased secretion of Th2 cytokines from T1/ST2 type 2 innate lymphoid cells is induced in the presence of IL-33 (5). Similarly, atopic dermatitis patient skin biopsies also show overexpression of IL-33, as do sites of allergic conjunctivitis and giant papillae (10). Allergic sensitization via rhinovirus can additionally induce IL-33 hypersecretion in the airway of human asthmatic patients (11). At the genetic level, IL-33 and ST2/ILR1 were the only two genes identified in multiple genome-wide studies to be consistently associated with asthmatic patients across a diverse variety of backgrounds and pathologies (12-16). Transgenic overexpression of IL-33 via a skin-selective promoter elicits atopic dermatitis-like inflammation (17). These data strongly implicate the IL-33/T1/ST2 pathway in the exacerbation of respiratory and skin allergy difficulties in humans.

Unregulated IL-33 production provokes a number of undesirable immune complications. For instance, overexpression of IL-33 has also been associated with liver fibrosis and ulcerative colitis in both mice and humans (18-21) and in arthritis in mice. (22). In fact, neutralizing IL-33 levels in mouse cisplatin-induced acute kidney injury (AKI) model for kidney inflammation through treatment with soluble T1/ST2 produced an overall reduction in proinflammatory responses as indicated by decreased infiltration of CD4T cells, serum creatinine and apoptotic and necrotic tissue injury (23). These data suggest that blocking the IL-33 pathway could serve as a therapeutic for inflammatory diseases.

Indeed, blocking IL-33 expression or pathway signaling evokes a protective effect in many mouse models of disease. This includes the attenuation of auto-immune responses such as graft versus host disease (GVHD)(24), reduced psoriasis-like plaque formation during skin inflammation (25), diminished colon inflammation and accompanying diarrhea in dextran sulphate sodium-induced colitis (19), and lowered expression of articular proinflammatory cytokines in autoantibody-induce arthritis (22). In each of these models, the administration of IL-33 further amplified the inappropriate aspects of the immune response, highlighting the deleterious role of the cytokine. Taken together, these data suggest the need for clinical investigations of the IL-33/ST2 pathway, particularly as human patients also exhibit elevated levels of IL-33 during episodes GVHD (24), psoriasis (26), and arthritis (27).

It is important to remember, however, that enthusiasm for IL-33/T1/ST2-driven therapies must also be tempered with caution. The deletion of T1/ST2, for example, nullifies the inherent protection of certain resistant mouse models to central nervous system autoimmune responses (e.g. EAE) (28) and protection against polymicrobial infections (29). By contrast, in a K/BxN serum transfer model of arthritis induction, joint inflammation was ameliorated in ST2 knockout mice, while IL-33 knockout animals experienced no such attenuation of the disease (30). IL-33-driven therapies, therefore, may likely require a very delicately balanced administration.

The IL-33/T1/ST2 axis is an intriguing immune pathway, with the potential to play a role in both induction and reduction of a given immune response. Further investigation of the conditions under which this pleiotropic cytokine regulates destruction or protection will enhance our ability to augment or suppress the immune response to a diverse variety of immunological complications.

 

See MD Biosciences commercially availible T1/ST2 monoclonal antibody!

 

References:

1) Oboki, K et al. Allergol Int. 2010 59, 143-160.

2) Gadani S.P et al. Neuron. 2015 Feb 18;85(4):703-9.

3) Moussion, C. et al. PLoS One. 2008 3, e3331.

4) Haraldsen, G., et al. Trends Immunol. 2009 30, 227-233.

5) Salimi, M. et al. J Exp Med. 2013 210, 2939-2950.

6) Haenuki, Y. et al. J Allergy Clin Immunol. 2012 130, 184-194 e111.

7) Halim, T. Y. et al. Immunity. 2014 40, 425-435.

8) Oboki, K. et al. Proc Natl Acad Sci U S A. 2010 107, 18581-18586.

9) Mjosberg, J. M. et al. Nat Immunol. 2001 12, 1055-1062.

10) Matsuda, A. et al. Invest Ophthalmol Vis Sci. 2009 50, 4646-4652.

11) Jackson, D. J. et al. Am J Respir Crit Care Med. 2014 190, 1373-1382.

12) Bonnelykke, K. et al. Nat Genet. 2014 46, 51-55.

13) Gudbjartsson, D. F. et al. Nat Genet. 2009 41, 342-347.

14) Moffatt, M. F. N et al. Engl J Med 2010 363, 1211-1221.

15) Ramasamy, A. et al. PLoS One. 2012 7, e44008.

16) Torgerson, D. G. et al. Nat Genet. 2011 43, 887-892.

17) Imai Y. et al. Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):13921-6.

18) Marvie, P. et al. J Cell Mol Med. 2010 Jun;14(6B):1726-39.

19) Pushparaj, P. N. et al. Immunology 2013 140, 70-77.

20) Beltrain, C.J. et al. Inflamm Bowel Dis. 2010 Jul;16(7):1097-107.

21) Kobori A et al. J Gastroenterol. 2010 Oct;45(10):999-1007.

22) Xu, D. et al. J Immunol 2010 184, 2620-2626.

23) Akcay, A. et al. J Am Soc Nephrol 2011 22, 2057-2067.

24) Reichenbach, D. K. et al. Blood 2015 125, 3183-3192.

25) Hueber, A. J. et al. Eur J Immunol. 2011 41, 2229-2237.

26) Mitsui, A. et al. Clin Exp Dermatol, 2015 12670.

27) Sellam, J. et al. Arthritis Rheumatol. 2014 66, 2015-2025.

28) Milovanovic, M. et al. PLoS One 7. 2012 e45225.

29) Buckley, J. M. et al. J Immunol. 2011 187, 4293-4299.

30) Kamradt, T. & Drube, S. Arthritis Res Ther. 2013 15, 115.

Topics: Dermal, Inflammation, Research Products, Infection, Acute Kidney Injury (AKI)