Metabolic Immunology

METABOLIC IMMUNOLOGYJess Aimee White

Metabolic Immunology

Also referred to as: Immunometabolism

Pathogenic defence is necessary for survival The bodies immune response involves key changes to metabolic

processes Immune mediators, such as cytokines, also dictate changes in

metabolism Including, the endocrine regulation of substrate utilisation (Schertzer

et al., 2014)

Research has provided insight into: How inflammation drives type 2 diabetes How adipose-tissue-derived mediators are involved in inflammation

and metabolic disease How immune cells act in adipose tissue How T-cell metabolism is related to T-cell fate Immunomodulatory strategies (Mathis et al., 2011).

Basic Role of Metabolism in the Immune System

Cell-intrinsic metabolic processes effect the performance of immune cells

Important in the control of immune cell number and function Immune cells use and respond to nutrients just like other cells

Metabolic states depend on energy levels. Uncoupling proteins play an important role in immunoprivilege

(Newell et al., 2006) Changes in metabolism (by oxidative stress or energy availability) will

initiate changes in immune recognition and the nature of immune responses (MacIver et al., 2013).

Pattern recognition receptors (PRRs) can integrate nutrient- and pathogen- sensing systems. Inflammasomes are thus, key regulators of metabolic inflammation

by working as metabolic danger sensors

Adipose Tissue and Adipokines

Adipokines are cytokines which are secreted by adipose tissue Adipose tissue, otherwise known as fat, is the connective tissue

composed of adipocytes

Members include: Leptin, Interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNFα)

Leptin is not appropriately considered an adipokine as they do not act on the immune system (Raucci et al., 2013)

Proinflammatory

They are signalling molecules that assist immune responses and stimulate the movement of cells towards specific sites of inflammation and infection.

Adipokine Examples

Trayhurn et al., 2006

Inflammasomes

“Inflammasomes are large intracellular multi-protein complexes that play a central role in innate immunity. They are key signalling platforms that detect pathogenic microorganisms and sterile stressors, and that activate the highly pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18.” – Latz et al., 2013

Tsutsui et al., 2010

The NLRP3 inflammasome: IL-1β and IL-18 production

Inflammasomes contain a member of the NOD-like receptor (NLR) family, including NLRP3 and IPAF

The NLR protein recruits the inflammasome-adaptor protein ASC

p10 and p20 caspase-1subunits assemble to form active caspase-1 heterotetramers

Once activated, caspase-1 promotes the maturation of the proinflammatory cytokines interleukin (IL)-1β and IL-18 (Benetti et al., 2013)

Following the activation of NLRP3, cells secrete large amounts of pro-inflammatory cytokines Cells will usually undergo caspase-1-induced cell death, which is also

known as pyroptosis.

Obesity Activates The NLRP3 Inflammasome

Obesity predisposes individuals to an range of chronic IL-1β-mediated metabolic diseases, including type 2 diabetes (T2D)

Obesity-induced inflammatory state has also been linked to the activation of adipose tissue macrophages (ATMs) within adipose tissue (Vandanmagsar et al., 2011)

Gene-deficient mice fed a high fat diet showed a reduced caspase-1 activation and pro-IL-1β expression in adipose tissue, and a loss of serum IL-18 production, when compared to the wild-type mice (Nardo et al., 2011)

A danger signal for NLRP3 activation in obesity is the increased presence of the lipid molecule ceramide (composed of sphingosides and fatty acids)

LPS-primed macrophages stimulated with ceramide therefore display NLRP3-dependent caspase-1 activation and production of IL-1β

(Choi et al., 2011)

NLRP3 Mediated Type 2 Diabetes

In macrophages, exogenous danger signals, such as an increase in saturated fatty acids, activate NLRP3 and trigger IL-1β release (Lee et al., 2012)

IL-1β deregulates insulin signalling, which potentially leads to insulin resistance in cells.

Increased expression of the NLRP3 inflammasome in ATMs during an obese state is related to the activation of T cells, including interferon (IFN-γ) in adipose tissue, which stimulates macrophage activation and systemic inflammation (Shahzad et al., 2014).

(Yang et al., 2012)

Shahzad et al., 2014

References Benetti, E., Chiaza, F., Patel, N.S.A. and Collino, M. (2013) The NLRP3 inflammasome as a novel player of the intercellular

crosstalk in metabolic disorder. Mediators of Inflammation. 2013: doi:10.1155/2013/678627 Choi, A.M.K. and Nakahira, K. (2011) Dampening insulin signalling by an NLRP3 ‘meta-flammasome’. Nature

Immunology. 12: 379-380 Lee, H.M., Kim, J.J., Kim, H.J., Shong, M., Ku, B.J. and Jo, E.K (2012) Unregulated NLRP3 inflammasome activation in

patients with type 2 diabetes. Diabetes. 62: 194-204 MacIver, N.J., Michalek, R.D. and Rathmell, J.C. (2013) Metabolic Regulation of T Lymphocytes. Annual Review of

Immunology. 31: 259-283 Mathis, D. and Shoelson, S.E. (2011) Immunometabolism: An emerging frontier. Nature Reviews Immunology. 11(2): 81 Nardo, D.D. and Latz, E. (NLRP3 inflammasomes link inflammation and metabolic disease. Trends in Immunology. 32(8):

373-379 Newell, M.K., Villalobos,-Menuey, E., Schweitzer, S.C., Harper, M.E. and Camley, R.E. (2006) Cellular metabolism as a

basis for immune privilege. Journal of Immune Based Therapies and Vaccines. 4(1): doi:10.1186/1476-8518-4-1 Raucci, R., Rusolo, F., Sharma, A., Colonna, G., Castello., G. and Costantini, S. (2013) Functional and structural features

of the adipokine family. Cytokine. 61(1): 1-14 R&D Systems (2013) Obesity-induced activation of the NLRP3 inflammasome promotes insulin resistance [online]

Available from: http://www.rndsystems.com/cb_detail_objectname_cb11i2_obesity_induced_activation_nlrp3.aspx [Accessed 25th November 2014]

Schertzer, J.D. and Steinberg, G.R. (2014) Immunometabolism: The interface of immune and metabolic responses in disease. Immunology and Cell Biology. 92: 303

Shahzad, K., Bock, F., Dong, W., Wang, H., Kopf, S., and Kohli, S. (2014) NLRP3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy. Kidney International. 2014: doi:10.1038/ki.2014.271

Trayhurn, P., Bing, C. and Wood, I.S. (2006) adipose tissue and adipokines – energy regulation from the human perspective. The journal of nutrition. 136(7):19355-19395

Tsutsui, H., Imamura, m., Fujimoto, J. and Nakanishi, K. (2010) The TLR4/TRIF-mediated activation of NLRP3 inflammasome underlies endotoxin-induced livery injury in mice. Gastroenterology Research and Practice. 2010: doi:10.1155/2010/641865

Vandanmagsar, B., Youm, Y.H., Ravussin, A., Galgani, J.E. and Stadler, K. (2011) The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nature Medicine. 17: 179-188

Yang, C.S., Shin, D.M. and Jo, E.K. (2012) The role of NLR-related protein 3 inflammasome in host defence and inflammatory diseases. International Neurology Journal. 16(1): 2-12

Questions