Local and Systemic Immune Responses Following Aspiration of Nickel Oxide Nanoparticles in a Humanized Toll-Like Receptor-4 Mouse Model

Details

• Personal Author:
  Aldinger JL ; Roach KA ; Roberts, Jennifer R. ; Stefaniak, Aleksandr B. ; Waggy C
• Description:
  Background and Purpose: It has been estimated that 20% of the global population exhibits contact sensitivity to nickel. Despite such prevalence in humans, recreating nickel allergy in laboratory rodents has proven challenging historically, ultimately limiting our understanding of many underlying immunological mechanisms responsible for the disorder. In 2010, it was discovered that species-specific differences in Toll-like receptor-4 (TLR-4) structure contribute to the discrepancies in susceptibility between mice and humans; subsequent findings in a humanized (h)TLR-4 mouse model demonstrated that the model more accurately depicts human immune responses to nickel in the skin, but the role of hTLR-4 in nickel's biological effects in other tissues remains unclear. Consequently, the primary goal of this study was to characterize alterations in various immune parameters in both sexes and genotypes of mice from the hTLR-4 colony following lung exposure to nickel. Methods: On 0d, a group of hTLR-4 negative and positive mice of both sexes (n=6) were exposed to vehicle control (dispersion media, DM) or nickel oxide nanoparticles (NiONP, 48 nm, one of three doses: 2.5, 5, or 20 µg) once by oropharyngeal aspiration. A set of mice from each sex/genotype combination was euthanized 1, 7, 14, or 28 d post-exposure. Bronchoalveolar lavage (BAL) was performed to evaluate cellular constituents and biochemical markers of inflammation within the airways. Blood was collected, circulating leukocyte profiles were characterized, and serum cytokine levels were evaluated. Finally, the lung-associated lymph nodes, thymus, and spleen were harvested, weighed, and phenotyped. Results: NiONP exposure resulted in dose-dependent increases in the total number of immune cells present in the lungs of all animals. Higher innate immune cell (e.g., neutrophils) influx was observed in all groups, but increases in the number and proportionality of lymphocytes in the BAL were only detected in hTLR-4 positive animals. Lymphocytes comprised 3.25% of the BAL cell pool in females at 14d (compared to 1.12% in DM, 2.13% in hTLR-4 negative) and 2.30% in males at 7 d (compared to 0.88% DM, 1.28% in hTLR-4 negative). Exposure to the 20 ug NiONP dose also induced significant increases in total cellularity of the lung-associated lymph nodes in all groups. In females, lymph node cell number peaked at 14 d, increasing 1.5-fold over DM control values in the hTLR-4 negative group (5.01x106) and 2.5-fold in hTLR-4 positive females (6.46x106). In males, lymph node cellularity increases were evident by 7 d, though responses were not as pronounced as those observed in females. Total cell number reached 1.2x control values (5.21x106) in the hTLR-4 negative group and 1.7x (5.62x106) in hTLR-4 positive males. NiONP exposure induced several notable changes in lymph node cellular composition as well-most of which were seen exclusively in hTLR-4 positive mice and were overall more pronounced in females. Increases in lymph node CD4+ T-cell and B-cell activation were observed in both females and males but increases in the proportionality of these two lymphocyte populations were only noted in hTLR-4 positive females. Cellular composition in the spleen exhibited similar alterations as those seen in the lymph nodes, except for one notable difference-in the lymph nodes, NiONP was associated with an increase in the CD4:8 T-cell ratio in hTLR-4 positive females and males, but in the spleen, this ratio was significantly decreased in hTLR-4 positive males. No clear relationship could be discerned between changes in the circulating leukocyte profile and any other parameter of the study; however, the few statistically significant changes observed occurred in the hTLR-4 positive groups. Conclusions: Overall, mice expressing hTLR-4 exhibited significantly enhanced immunological responsivity to NiONP compared to non-carriers. In general, female mice were more susceptible to nickel-induced immune alterations in the lung and associated lymphoid tissues, as well as in the spleen and blood. These findings, in combination with our previous findings in the skin, suggest that the hTLR-4 mouse model exhibits a heighted degree of reactivity to nickel that more closely resembles human responses to the metal, and thus, represents an improved approach for studying the general toxicity and allergenicity of nickel and its various formulations (e.g., nanoparticulates, salts, etc.) in vivo. [Description provided by NIOSH]
• Subjects:
  Hypersensitivity Immune System Laboratories Occupational Health Safety Toxicology
• Keywords:
  Allergic Reactions Immune Reaction Laboratory Animals Nanoparticles Nickel Oxide
• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division ; RHD - Respiratory Health Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  198
• NIOSHTIC Number:
  nn:20069340
• Citation:
  Toxicologist 2024 Mar; 198(S1):315
• CAS Registry Number:
  Nickel monoxide (CAS RN 1313-99-1)
• Federal Fiscal Year:
  2024
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 63rd Annual Meeting & ToxExpo, March 10-14, 2024, Salt Lake City, Utah
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:96c0f7f83225cbbb5dbd59c1cf56566076ebc0caa436078fd7e4d011591cc0a3b683d2e33f1278de103c1646d17ac304ef7660bf10547e519123f31c3bfd1741
• Download URL:
  https://stacks.cdc.gov/view/cdc/207838/cdc_207838_DS1.pdf
• File Type:
  [PDF - 483.74 KB ]