Cell Stress and Chaperones

, Volume 23, Issue 5, pp 1129–1135 | Cite as

Topical heat shock protein 70 prevents imiquimod-induced psoriasis-like inflammation in mice

  • Federico G. Seifarth
  • Julia E.-M. Lax
  • Jennifer Harvey
  • Paul E. DiCorleto
  • M. Elaine Husni
  • Unnikrishnan M. Chandrasekharan
  • Michael Tytell
Short Communication


Psoriasis is a chronic inflammatory skin disease with systemic manifestations and potential genetic etiology. The newest treatments utilize antibodies against one of several cytokines known to underlie the inflammatory signaling molecules that produce the skin and systemic symptoms. However, these agents must be regularly injected, and they may compromise the normal responses of the immune system. Furthermore, they do not address the causes of the abnormal immunoregulatory responses of the disease because the etiology is not yet completely understood. In this short-term treatment study, the potential anti-inflammatory activity of an alfalfa-derived Hsp70-containing skin cream (aHsp70) was tested on imiquimod (IMQ)-induced psoriasis-like lesions in wild-type mice. Treatment of the mice with the aHsp70 skin cream simultaneously with the imiquimod application mitigated the induction of psoriatic-like lesions and correlated with altered expression of various skin cytokines.


Hsp70 Alfalfa Psoriasis Skin cream Anti-inflammatory 


Funding information

This research was supported by the Cleveland Clinic (Cleveland, OH), National Psoriasis Foundation (discovery grant 2016 to U. C.) and Alfa Biogene International, B.V. (Baarn, Netherlands).

Compliance with ethical standards

All experiments were approved by the institutional animal care and use.


  1. Baliwag J, Barnes DH, Johnston A (2015) Cytokines in psoriasis. Cytokine 73:342–350. CrossRefPubMedPubMedCentralGoogle Scholar
  2. Beutner KR, Tyring S (1997) Human Papillomavirus and Human Disease. Am J Med 102(5):9–15CrossRefPubMedGoogle Scholar
  3. Bhatia A, O'Brien K, Guo J, Lincoln V, Kajiwara C, Chen M, Woodley DT, Udono H, Li W (2018) Extracellular and non-chaperone function of heat shock protein-90α is required for skin wound healing. J Invest Dermatol 138:423–433. CrossRefPubMedGoogle Scholar
  4. Bukau B and Mayer MP (2005) Recovery of a heat shock protein. Patent publication #EP 1531160 A1,
  5. Burden-Teh E, Thomas KS, Ratib S, Thomas KS, Ratib S, Grindlay D, Adaji E, Murphy R (2016) The epidemiology of childhood psoriasis: a scoping review. Br J Dermatol 174:1242–1257. CrossRefPubMedGoogle Scholar
  6. Calderwood SK, Gong J, Murshid A (2016) Extracellular HSPs: the complicated roles of extracellular HSPs in immunity. Front Immunol 7:159. PubMedPubMedCentralCrossRefGoogle Scholar
  7. Davidovici BB, Sattar N, Prinz J, Puig L, Emery P, Barker JN, van de Kerkhof P, Stâhle M, Nestle FO, Girolomoni G, Kreuger JG (2010) Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol 130:1785–1796. CrossRefPubMedGoogle Scholar
  8. Deng Y, Chang C, Lu Q (2016) The inflammatory response in psoriasis: a comprehensive review. Clin Rev Allergy Immunol 50:377–389. CrossRefPubMedGoogle Scholar
  9. Fanti PA, Dika E, Vaccari S, Miscail C, Varotti C (2006) Generalized psoriasis induced by topical treatment of actinic keratosis with imiquimod. Int J Dermatol 45:1464–1465. CrossRefPubMedGoogle Scholar
  10. Farne HA, Wilson A, Powell C, Bax L, Milan SJ (2017) Anti-IL5 therapies for asthma. Cochrane Database Syst Rev 9:CD010834. PubMedCrossRefGoogle Scholar
  11. Gallo RL, Nakatsuji T (2011) Microbial symbiosis with the innate immune defense system of the skin. J Investig Dermatol 131:1974–1980. CrossRefPubMedGoogle Scholar
  12. Geisse J, Caro I, Lindholm J, Golitz L, Stampone P, Owens M (2004) Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol 50:722–733. CrossRefPubMedGoogle Scholar
  13. Greenfeder S, Umland SP, Cuss FM, Chapman RW, Egan RW (2001) Th2 cytokines and asthma. The role of interleukin-5 in allergic eosinophilic disease. Respir Res 2:71–79CrossRefPubMedPubMedCentralGoogle Scholar
  14. Gudjonsson JE, Johnston A, Dyson M, Valdimarsson H, Elder JT (2007) Mouse models of psoriasis. J Invest Dermatol 127:1292–1308. CrossRefPubMedGoogle Scholar
  15. Guzhova IV, Margulis BA (2016) HSP70-based anti-cancer immunotherapy. Hum Vaccin Immunother 12:2529–2535. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Jin W, Dong C (2013) IL-17 cytokines in immunity and inflammation. Emerg Microbes Infect 2:e60. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Lowes MA, Suarez-Farinas M, Krueger JG (2014) Immunology of psoriasis. Annu Rev Immunol 32:227–255. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Monin L, Gaffen SL (2017) Interleukin 17 family cytokines: signaling mechanisms, biological activities, and therapeutic implications. Cold Spring Harb Perspect Biol.
  19. Mushtaq S, Naqvi ZA, Siddiqui AA, Ahmed N (2011) Albumin precursor and Hsp70 modulate corneal wound healing in an organ culture model. Acta Histochem 113:36–42. CrossRefPubMedGoogle Scholar
  20. Nestle FO, Kaplan DH, Barker J (2009) Psoriasis. N Engl J Med 361:496–509. CrossRefPubMedGoogle Scholar
  21. Noben-Trauth N, Kropf P, Muller I (1996) Susceptibility to Leishmania major infection in interleukin-4-deficient mice. Science 271:987–990CrossRefPubMedGoogle Scholar
  22. Park CJ, Seo YS (2015) Heat shock proteins: a review of the molecular chaperones for plant immunity. Plant Pathol J 3:323–333. CrossRefGoogle Scholar
  23. Perera GK, Di Meglio P, Nestle FO. Psoriasis. Annu Rev Pathol 2012;7:385–422
  24. Rajan N, Langtry JA (2006) Generalized exacerbation of psoriasis associated with imiquimod cream treatment of superficial basal cell carcinomas. Clin Exp Dermatol 31(1):140–141. CrossRefPubMedGoogle Scholar
  25. Schon MP (2008) Animal models of psoriasis: a critical appraisal. Exp Dermatol 17:703–712. CrossRefPubMedGoogle Scholar
  26. Seifarth F and Lax J (2014) Filtration of a liquid comprising a plant stress protein. Publication # EP2417153 B1.
  27. Sharma J, Balakrishnan L, Datta KK, Sahasrabuddhe NA, Khan AA, Sahu A, Singhal A, Getnet D, Raju R, Chatterjee A, Gowda H, Keshava Prasad TS, Shankar S, Pandey A (2015) A knowledgebase resource for interleukin-17 family mediated signaling. J Cell Commun Signal 9:291–296. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Sonnenberg GF, Nair MG, Kirn TJ, Zaph C, Fouser LA, Artis D (2010) Pathological versus protective functions of IL-22 in airway inflammation are regulated by IL-17A. J ExpMed 207:1293–1305. CrossRefGoogle Scholar
  29. Tytell M, Davis AT, Giles J, Snider LC, Xiao R, Dozier SG, Presley TD, Kavanagh K (2017) Alfalfa-derived HSP70 administered intranasally improves insulin sensitivity in mice. Cell Stress and Chaperones 70:1–6. CrossRefGoogle Scholar
  30. van der Fits L, Mourits S, Voerman JS, Kant M, Boon L, Laman JD, Comelissen F, Mus AM, Florencia E, Prens EP, Lubberts E (2009) Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL23/IL17 axis. J Immunol 182:5836–5845. CrossRefPubMedGoogle Scholar
  31. van Eden W, Spiering R, Broere F, van der Zee R (2012) A case of mistaken identity: HSPs are no DAMPs but DAMPERs. Cell Stress and Chaperones 17:281–292. CrossRefPubMedGoogle Scholar
  32. Wu JK, Siller G, Strutton G (2004) Psoriasis induced by topical imiquimod. Australas J Dermatol 45:47–50CrossRefPubMedGoogle Scholar
  33. Wu JJ, Lynde CW, Kleyn CE, Iversen L, van der Walt JM, Carvalho A, Kirby B, Bissonette R (2016) Identification of key research needs for topical therapy treatment of psoriasis—a consensus paper by the International Psoriasis Council. J Eur Acad Dermatol Venereol 30:1115–1119. CrossRefPubMedGoogle Scholar
  34. Yawalkar N, Shrikhande M, Hari Y, Nievergelt H, Braathen LR, Pichler WJ (2000) Evidence for a role for IL-5 and eotaxin in activating and recruiting eosinophils in drug-induced cutaneous eruptions. J Allergy Clin Immunol 106:1171–1176. CrossRefPubMedGoogle Scholar
  35. Yu WW, Cao SN, Zang CX, Wang L, Yang HY, Bao XQ, Zhang D (2018) Heat shock protein 70 suppresses neuroinflammation induced by alpha-synuclein in astrocytes. Mol Cell Neurosci 86:58–64. CrossRefPubMedGoogle Scholar
  36. Zhe Y, Li Y, Liu D, Su DM, Liu JG Li HY (2016) Extracellular HSP70-peptide complexes promote the proliferation of hepatocellular carcinoma cells via TLR2/4/JNK1/2MAPK pathway. Tumor Biol 37:13951–13959. CrossRefGoogle Scholar

Copyright information

© Cell Stress Society International 2018

Authors and Affiliations

  1. 1.Department of Pediatric SurgeryCleveland Clinic Children’s HospitalClevelandUSA
  2. 2.Department of Pediatric SurgeryKalispell Regional HealthcareKalispellUSA
  3. 3.Alfa Biogene International B.V.BaarnThe Netherlands
  4. 4.Department of Cellular and Molecular MedicineCleveland Clinic Lerner Research Institute and Cleveland Clinic Lerner College of Medicine of Case Western Reserve UniversityClevelandUSA
  5. 5.Department of Rheumatic and Immunologic DiseasesCleveland ClinicClevelandUSA
  6. 6.Division of Research and Sponsored ProgramsKent State UniversityKentUSA
  7. 7.Department of Neurobiology and AnatomyWake Forest University School of MedicineWinston-SalemUSA

Personalised recommendations