An overview of metabolic immunology and its role in the progression of type 2 diabetes.

1. METABOLIC IMMUNOLOGY
Jess Aimee White

2. 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).

3. 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

4. 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.

5. Adipokine Examples
Trayhurn et al., 2006

6. 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

7. 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.

8. 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

9. (Choi et al., 2011)

10. 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)

12. Shahzad et al., 2014

13. 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

14. Questions